The University of Nebraska-Lincoln proposes to establish the Molecular Mechanisms of Disease (MMoD) predoctoral training program to provide innovative training and career development in biomedical research centered on molecular interactions and chemical transformations. The program bridges a nine-state gap in the NIH training focus of Cellular, Biochemical, and Molecular Sciences. The goal of the program is to develop outstanding new scientists who work in collaborative multi-disciplinary teams to research disease mechanisms using quantitative approaches that ultimately yield tangible strategies for prevention and therapy. To accomplish this goal, the program will recruit high-quality, motivated predoctoral trainees with a strong interest in the underlying causes of human disease and engage them in mentored, cutting-edge research. The specific aims are to: (1) Provide a rigorous curriculum and innovative, collaborative research opportunities for sixteen predoctoral trainees per year (eight NIH-supported and eight institutionally supported) to become experts in the mechanistic study of human disease; (2) Cultivate an interactive training environment that emphasizes development of outstanding skills in professional networking, grantsmanship, leadership, and written and oral communication; (3) Support collaborative training efforts of mentors in four areas of mechanistic disease research emphasis: molecular signaling, metabolic integrity, oxidative stress, and disease microenvironment. NIH support will span two years of a five-year program for trainees with undergraduate laboratory experience and one year of graduate-level coursework prior to the T32 training period. Selection of new trainees will be competitive, based on strong academic record, research progress and potential, and an original collaborative proposal bridging disciplinary boundaries for innovative thesis research. The MMoD mentoring team spans seven departments and three colleges and includes 28 faculty members, all with strong histories in biomedical research funding and graduate student mentoring. Trainees will complete four research rotations in year 1 before choosing a faculty mentor representing one of the four emphasis areas. Trainees will take a flexible core curriculum: Metabolic Function and Dysfunction, one Quantitative Biology course from an approved core, and two Macromolecules courses from an approved core. Through these courses, they will receive formal training in grantsmanship, scientific writing, and research and journal article presentations. They will also be provided with unique entrepreneurial learning and teaching opportunities and will organize an annual symposium centered on the meeting of the program's external advisory committee. The MMoD program will provide a framework that enables trainees to assemble a broad knowledge base; actively seek research collaborations; produce an outstanding record of original published research; and develop presentation, proposal-writing, and leadership skills that will position them for future excellence as independent researchers focused on mechanisms of disease progression.